The Peptidome of Behçet's Disease–Associated HLA–B51:01 Includes Two Subpeptidomes Differentially Shaped by Endoplasmic Reticulum Aminopeptidase 1
Objective To characterize the peptidome of the Behçet's disease–associated HLA–B*51:01 allotype as well as the differential features of major peptide subsets and their distinct endoplasmic reticulum aminopeptidase 1 (ERAP‐1)–mediated processing. Methods The endogenous B*51:01‐bound peptidome wa...
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| Veröffentlicht in: | Arthritis & rheumatology (Hoboken, N.J.) N.J.), 2016-02, Vol.68 (2), p.505-515 |
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| creator | Guasp, Pablo Alvarez‐Navarro, Carlos Gomez‐Molina, Patricia Martín‐Esteban, Adrian Marcilla, Miguel Barnea, Eilon Admon, Arie López de Castro, José A. |
| description | Objective
To characterize the peptidome of the Behçet's disease–associated HLA–B*51:01 allotype as well as the differential features of major peptide subsets and their distinct endoplasmic reticulum aminopeptidase 1 (ERAP‐1)–mediated processing.
Methods
The endogenous B*51:01‐bound peptidome was characterized from 721.221 transfectant cells, after affinity chromatography and acid extraction, by tandem mass spectrometry. Recombinant ERAP‐1 variants were used to digest synthetic B*51:01 ligands. HLA and transporter associated with antigen processing (TAP) binding affinities of peptide ligands were calculated with well‐established algorithms. ERAP‐1 and ERAP‐2 from 721.221 cells were characterized by genomic sequencing and Western blotting.
Results
The B*51:01 peptidome consisted of 29.5% octamers, 61.7% nonamers, 4.8% decamers, and 4.0% longer peptides. The major peptide motif consisted of Pro and Ala at position 2, aliphatic/aromatic position 3 residues, and Val and Ile at the C‐terminal position. The ligands with Pro or Ala at position 2 constituted 2 distinct subpeptidomes. Peptides with Pro at position 2 showed higher affinity for B*51:01 and lower affinity for TAP than those with Ala at position 2. Most important, both peptide subsets differed drastically in the susceptibility of their position 1 residues to ERAP‐1, revealing a distinct influence of this enzyme on both subpeptidomes, which may alter their balance, affecting the global affinity of B*51:01–peptide complexes.
Conclusion
ERAP‐1 has a significant influence on the B*51:01 peptidome and its affinity. This influence is based on very distinct effects on the 2 subpeptidomes, whereby only peptides in the subpeptidome with Ala at position 2 are extensively destroyed, except when their position 1 residues are ERAP‐1 resistant. This pattern provides a mechanism for the epistatic association of ERAP‐1 and B*51:01 in Behçet's disease. |
| doi_str_mv | 10.1002/art.39430 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_1760925800</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>3932107171</sourcerecordid><originalsourceid>FETCH-LOGICAL-c3490-57018bf67d7c2db20a75ac33f324b46f12619fac1f46bb2527534cef7fe5889e3</originalsourceid><addsrcrecordid>eNp1kU1O3DAYhq0KVBCw6AUqS10AiwH_xE7SXfhpQRqJCqbryHE-a4ycOI0TodlxBxYcoQfpTXqSegjDohLefNan531s6UXoEyUnlBB2qvrhhOcJJx_QLuNMzgQjYmtzpzndQQch3JN48pRIIj6iHSa5JJxlu-h5sQT8A7rB1r4B7A0-g-Wf3zAcBnxhA6gAfx-fihC8tmqAGl_Ni7g4E_Qrofi61W6sIeDFg8d3Y9VtROuwMdBDO1jl3ArfLVUX09UKX7a175wKjdX4FgarRzc2uGhs66d4fBLTfbRtlAtw8Dr30M9vl4vzq9n85vv1eTGfaZ7kZCZSQrPKyLRONasrRlQqlObccJZUiTSUSZobpalJZFUxwVLBEw0mNSCyLAe-h44mb9f7XyOEoWxs0OCcasGPoaSpJDkTGSER_fIfeu_Hvo2_i5TI127KI3U8Ubr3IfRgyq63jepXJSXlurAyFla-FBbZz6_GsWqgfiM39UTgdAIerIPV-6ayuF1Myn_Jz6F1</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>1759527513</pqid></control><display><type>article</type><title>The Peptidome of Behçet's Disease–Associated HLA–B51:01 Includes Two Subpeptidomes Differentially Shaped by Endoplasmic Reticulum Aminopeptidase 1</title><source>MEDLINE</source><source>Wiley Blackwell Single Titles</source><source>Alma/SFX Local Collection</source><creator>Guasp, Pablo ; Alvarez‐Navarro, Carlos ; Gomez‐Molina, Patricia ; Martín‐Esteban, Adrian ; Marcilla, Miguel ; Barnea, Eilon ; Admon, Arie ; López de Castro, José A.</creator><creatorcontrib>Guasp, Pablo ; Alvarez‐Navarro, Carlos ; Gomez‐Molina, Patricia ; Martín‐Esteban, Adrian ; Marcilla, Miguel ; Barnea, Eilon ; Admon, Arie ; López de Castro, José A.</creatorcontrib><description>Objective
To characterize the peptidome of the Behçet's disease–associated HLA–B*51:01 allotype as well as the differential features of major peptide subsets and their distinct endoplasmic reticulum aminopeptidase 1 (ERAP‐1)–mediated processing.
Methods
The endogenous B*51:01‐bound peptidome was characterized from 721.221 transfectant cells, after affinity chromatography and acid extraction, by tandem mass spectrometry. Recombinant ERAP‐1 variants were used to digest synthetic B*51:01 ligands. HLA and transporter associated with antigen processing (TAP) binding affinities of peptide ligands were calculated with well‐established algorithms. ERAP‐1 and ERAP‐2 from 721.221 cells were characterized by genomic sequencing and Western blotting.
Results
The B*51:01 peptidome consisted of 29.5% octamers, 61.7% nonamers, 4.8% decamers, and 4.0% longer peptides. The major peptide motif consisted of Pro and Ala at position 2, aliphatic/aromatic position 3 residues, and Val and Ile at the C‐terminal position. The ligands with Pro or Ala at position 2 constituted 2 distinct subpeptidomes. Peptides with Pro at position 2 showed higher affinity for B*51:01 and lower affinity for TAP than those with Ala at position 2. Most important, both peptide subsets differed drastically in the susceptibility of their position 1 residues to ERAP‐1, revealing a distinct influence of this enzyme on both subpeptidomes, which may alter their balance, affecting the global affinity of B*51:01–peptide complexes.
Conclusion
ERAP‐1 has a significant influence on the B*51:01 peptidome and its affinity. This influence is based on very distinct effects on the 2 subpeptidomes, whereby only peptides in the subpeptidome with Ala at position 2 are extensively destroyed, except when their position 1 residues are ERAP‐1 resistant. This pattern provides a mechanism for the epistatic association of ERAP‐1 and B*51:01 in Behçet's disease.</description><identifier>ISSN: 2326-5191</identifier><identifier>EISSN: 2326-5205</identifier><identifier>DOI: 10.1002/art.39430</identifier><identifier>PMID: 26360328</identifier><language>eng</language><publisher>United States: Wiley Subscription Services, Inc</publisher><subject>Aminopeptidases - genetics ; Aminopeptidases - metabolism ; ATP-Binding Cassette Transporters - metabolism ; Behcet Syndrome - metabolism ; Cell Line ; Chromatography, Affinity ; Genotype ; HLA-B51 Antigen - metabolism ; Humans ; Minor Histocompatibility Antigens ; Peptides - metabolism ; Polymorphism, Single Nucleotide ; Tandem Mass Spectrometry</subject><ispartof>Arthritis & rheumatology (Hoboken, N.J.), 2016-02, Vol.68 (2), p.505-515</ispartof><rights>2016, American College of Rheumatology</rights><rights>2016, American College of Rheumatology.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c3490-57018bf67d7c2db20a75ac33f324b46f12619fac1f46bb2527534cef7fe5889e3</citedby><cites>FETCH-LOGICAL-c3490-57018bf67d7c2db20a75ac33f324b46f12619fac1f46bb2527534cef7fe5889e3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fart.39430$$EPDF$$P50$$Gwiley$$H</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fart.39430$$EHTML$$P50$$Gwiley$$H</linktohtml><link.rule.ids>314,780,784,1417,27924,27925,45574,45575</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/26360328$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Guasp, Pablo</creatorcontrib><creatorcontrib>Alvarez‐Navarro, Carlos</creatorcontrib><creatorcontrib>Gomez‐Molina, Patricia</creatorcontrib><creatorcontrib>Martín‐Esteban, Adrian</creatorcontrib><creatorcontrib>Marcilla, Miguel</creatorcontrib><creatorcontrib>Barnea, Eilon</creatorcontrib><creatorcontrib>Admon, Arie</creatorcontrib><creatorcontrib>López de Castro, José A.</creatorcontrib><title>The Peptidome of Behçet's Disease–Associated HLA–B51:01 Includes Two Subpeptidomes Differentially Shaped by Endoplasmic Reticulum Aminopeptidase 1</title><title>Arthritis & rheumatology (Hoboken, N.J.)</title><addtitle>Arthritis Rheumatol</addtitle><description>Objective
To characterize the peptidome of the Behçet's disease–associated HLA–B*51:01 allotype as well as the differential features of major peptide subsets and their distinct endoplasmic reticulum aminopeptidase 1 (ERAP‐1)–mediated processing.
Methods
The endogenous B*51:01‐bound peptidome was characterized from 721.221 transfectant cells, after affinity chromatography and acid extraction, by tandem mass spectrometry. Recombinant ERAP‐1 variants were used to digest synthetic B*51:01 ligands. HLA and transporter associated with antigen processing (TAP) binding affinities of peptide ligands were calculated with well‐established algorithms. ERAP‐1 and ERAP‐2 from 721.221 cells were characterized by genomic sequencing and Western blotting.
Results
The B*51:01 peptidome consisted of 29.5% octamers, 61.7% nonamers, 4.8% decamers, and 4.0% longer peptides. The major peptide motif consisted of Pro and Ala at position 2, aliphatic/aromatic position 3 residues, and Val and Ile at the C‐terminal position. The ligands with Pro or Ala at position 2 constituted 2 distinct subpeptidomes. Peptides with Pro at position 2 showed higher affinity for B*51:01 and lower affinity for TAP than those with Ala at position 2. Most important, both peptide subsets differed drastically in the susceptibility of their position 1 residues to ERAP‐1, revealing a distinct influence of this enzyme on both subpeptidomes, which may alter their balance, affecting the global affinity of B*51:01–peptide complexes.
Conclusion
ERAP‐1 has a significant influence on the B*51:01 peptidome and its affinity. This influence is based on very distinct effects on the 2 subpeptidomes, whereby only peptides in the subpeptidome with Ala at position 2 are extensively destroyed, except when their position 1 residues are ERAP‐1 resistant. This pattern provides a mechanism for the epistatic association of ERAP‐1 and B*51:01 in Behçet's disease.</description><subject>Aminopeptidases - genetics</subject><subject>Aminopeptidases - metabolism</subject><subject>ATP-Binding Cassette Transporters - metabolism</subject><subject>Behcet Syndrome - metabolism</subject><subject>Cell Line</subject><subject>Chromatography, Affinity</subject><subject>Genotype</subject><subject>HLA-B51 Antigen - metabolism</subject><subject>Humans</subject><subject>Minor Histocompatibility Antigens</subject><subject>Peptides - metabolism</subject><subject>Polymorphism, Single Nucleotide</subject><subject>Tandem Mass Spectrometry</subject><issn>2326-5191</issn><issn>2326-5205</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2016</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp1kU1O3DAYhq0KVBCw6AUqS10AiwH_xE7SXfhpQRqJCqbryHE-a4ycOI0TodlxBxYcoQfpTXqSegjDohLefNan531s6UXoEyUnlBB2qvrhhOcJJx_QLuNMzgQjYmtzpzndQQch3JN48pRIIj6iHSa5JJxlu-h5sQT8A7rB1r4B7A0-g-Wf3zAcBnxhA6gAfx-fihC8tmqAGl_Ni7g4E_Qrofi61W6sIeDFg8d3Y9VtROuwMdBDO1jl3ArfLVUX09UKX7a175wKjdX4FgarRzc2uGhs66d4fBLTfbRtlAtw8Dr30M9vl4vzq9n85vv1eTGfaZ7kZCZSQrPKyLRONasrRlQqlObccJZUiTSUSZobpalJZFUxwVLBEw0mNSCyLAe-h44mb9f7XyOEoWxs0OCcasGPoaSpJDkTGSER_fIfeu_Hvo2_i5TI127KI3U8Ubr3IfRgyq63jepXJSXlurAyFla-FBbZz6_GsWqgfiM39UTgdAIerIPV-6ayuF1Myn_Jz6F1</recordid><startdate>201602</startdate><enddate>201602</enddate><creator>Guasp, Pablo</creator><creator>Alvarez‐Navarro, Carlos</creator><creator>Gomez‐Molina, Patricia</creator><creator>Martín‐Esteban, Adrian</creator><creator>Marcilla, Miguel</creator><creator>Barnea, Eilon</creator><creator>Admon, Arie</creator><creator>López de Castro, José A.</creator><general>Wiley Subscription Services, Inc</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QL</scope><scope>7QP</scope><scope>7T5</scope><scope>7TM</scope><scope>7U7</scope><scope>C1K</scope><scope>H94</scope><scope>K9.</scope><scope>7X8</scope></search><sort><creationdate>201602</creationdate><title>The Peptidome of Behçet's Disease–Associated HLA–B51:01 Includes Two Subpeptidomes Differentially Shaped by Endoplasmic Reticulum Aminopeptidase 1</title><author>Guasp, Pablo ; Alvarez‐Navarro, Carlos ; Gomez‐Molina, Patricia ; Martín‐Esteban, Adrian ; Marcilla, Miguel ; Barnea, Eilon ; Admon, Arie ; López de Castro, José A.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c3490-57018bf67d7c2db20a75ac33f324b46f12619fac1f46bb2527534cef7fe5889e3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Aminopeptidases - genetics</topic><topic>Aminopeptidases - metabolism</topic><topic>ATP-Binding Cassette Transporters - metabolism</topic><topic>Behcet Syndrome - metabolism</topic><topic>Cell Line</topic><topic>Chromatography, Affinity</topic><topic>Genotype</topic><topic>HLA-B51 Antigen - metabolism</topic><topic>Humans</topic><topic>Minor Histocompatibility Antigens</topic><topic>Peptides - metabolism</topic><topic>Polymorphism, Single Nucleotide</topic><topic>Tandem Mass Spectrometry</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Guasp, Pablo</creatorcontrib><creatorcontrib>Alvarez‐Navarro, Carlos</creatorcontrib><creatorcontrib>Gomez‐Molina, Patricia</creatorcontrib><creatorcontrib>Martín‐Esteban, Adrian</creatorcontrib><creatorcontrib>Marcilla, Miguel</creatorcontrib><creatorcontrib>Barnea, Eilon</creatorcontrib><creatorcontrib>Admon, Arie</creatorcontrib><creatorcontrib>López de Castro, José A.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>Immunology Abstracts</collection><collection>Nucleic Acids Abstracts</collection><collection>Toxicology Abstracts</collection><collection>Environmental Sciences and Pollution Management</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>MEDLINE - Academic</collection><jtitle>Arthritis & rheumatology (Hoboken, N.J.)</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Guasp, Pablo</au><au>Alvarez‐Navarro, Carlos</au><au>Gomez‐Molina, Patricia</au><au>Martín‐Esteban, Adrian</au><au>Marcilla, Miguel</au><au>Barnea, Eilon</au><au>Admon, Arie</au><au>López de Castro, José A.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Peptidome of Behçet's Disease–Associated HLA–B51:01 Includes Two Subpeptidomes Differentially Shaped by Endoplasmic Reticulum Aminopeptidase 1</atitle><jtitle>Arthritis & rheumatology (Hoboken, N.J.)</jtitle><addtitle>Arthritis Rheumatol</addtitle><date>2016-02</date><risdate>2016</risdate><volume>68</volume><issue>2</issue><spage>505</spage><epage>515</epage><pages>505-515</pages><issn>2326-5191</issn><eissn>2326-5205</eissn><abstract>Objective
To characterize the peptidome of the Behçet's disease–associated HLA–B*51:01 allotype as well as the differential features of major peptide subsets and their distinct endoplasmic reticulum aminopeptidase 1 (ERAP‐1)–mediated processing.
Methods
The endogenous B*51:01‐bound peptidome was characterized from 721.221 transfectant cells, after affinity chromatography and acid extraction, by tandem mass spectrometry. Recombinant ERAP‐1 variants were used to digest synthetic B*51:01 ligands. HLA and transporter associated with antigen processing (TAP) binding affinities of peptide ligands were calculated with well‐established algorithms. ERAP‐1 and ERAP‐2 from 721.221 cells were characterized by genomic sequencing and Western blotting.
Results
The B*51:01 peptidome consisted of 29.5% octamers, 61.7% nonamers, 4.8% decamers, and 4.0% longer peptides. The major peptide motif consisted of Pro and Ala at position 2, aliphatic/aromatic position 3 residues, and Val and Ile at the C‐terminal position. The ligands with Pro or Ala at position 2 constituted 2 distinct subpeptidomes. Peptides with Pro at position 2 showed higher affinity for B*51:01 and lower affinity for TAP than those with Ala at position 2. Most important, both peptide subsets differed drastically in the susceptibility of their position 1 residues to ERAP‐1, revealing a distinct influence of this enzyme on both subpeptidomes, which may alter their balance, affecting the global affinity of B*51:01–peptide complexes.
Conclusion
ERAP‐1 has a significant influence on the B*51:01 peptidome and its affinity. This influence is based on very distinct effects on the 2 subpeptidomes, whereby only peptides in the subpeptidome with Ala at position 2 are extensively destroyed, except when their position 1 residues are ERAP‐1 resistant. This pattern provides a mechanism for the epistatic association of ERAP‐1 and B*51:01 in Behçet's disease.</abstract><cop>United States</cop><pub>Wiley Subscription Services, Inc</pub><pmid>26360328</pmid><doi>10.1002/art.39430</doi><tpages>11</tpages></addata></record> |
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| identifier | ISSN: 2326-5191 |
| ispartof | Arthritis & rheumatology (Hoboken, N.J.), 2016-02, Vol.68 (2), p.505-515 |
| issn | 2326-5191 2326-5205 |
| language | eng |
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| source | MEDLINE; Wiley Blackwell Single Titles; Alma/SFX Local Collection |
| subjects | Aminopeptidases - genetics Aminopeptidases - metabolism ATP-Binding Cassette Transporters - metabolism Behcet Syndrome - metabolism Cell Line Chromatography, Affinity Genotype HLA-B51 Antigen - metabolism Humans Minor Histocompatibility Antigens Peptides - metabolism Polymorphism, Single Nucleotide Tandem Mass Spectrometry |
| title | The Peptidome of Behçet's Disease–Associated HLA–B51:01 Includes Two Subpeptidomes Differentially Shaped by Endoplasmic Reticulum Aminopeptidase 1 |
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